Cryptorchidism, or undescended testis, is one of the most common male congenital anomalies, occurring in 2-4% of boys. It is non-syndromic and unilateral in the majority of cases, yet is often associated with bilateral impairment of germ cell development and subsequent infertility and/or malignancy. Neither the physiology nor the pathogenesis of this complex and heterogeneous disease are well understood but available data suggest the presence of multiple susceptibility loci. In addition, estrogens, antiandrogens and many environmental pollutants with endocrine-disrupting effects produce cryptorchidism in experimental animals after fetal exposure, it is likely that manifestation of the human disease is the result of gene-environment interactions. Several genes have been identified as strong candidates for cryptorchidism in targeted deletion studies. These include insl3, Great/LGR8, Desrt/MRF2, hoxA10 and hoxA11. We hypothesize that allelic variants in these genes are associated with susceptibility.to cryptorchidism and that this risk is modulated by the fetal hormonal milieu, which can be altered by genetic as well as extrinsic environmental factors. The overall goals of this project are to to elucidate the molecular mechanisms of normal and abnormal testicular descent in a rat model and to initiate a case-control study to measure biomarkers of effect and candidate genes that are associated with human cryptorchidism. Specific aims will be to: (1) screen candidate genes for cryptorchidism, identified from differential expression studies and other rodent models, for mutations using DHPLC and sequencing in a rat model of cryptorchidism; (2) initiate a case-control study of cryptorchidism to study biomarkers of exposure and effect including (a) expression of androgen and estrogen receptors using real time RT-PCR and (b) germ cell differentiation using FACS analysis of spermatogonial markers in target tissues and (3) identify and study allelic variants in candidate genes for cryptorchidism using a case-control design that will be validated by transmission disequalibrium testing. The long-term goals of this work will be to study gene-environment interaction in the etiology of cryptorchidism and to identify, predict and, when possible, minimize risk factors that contribute to this common disease.